This project will utilize techniques of molecular and cell biology to examine the mechanisms by which hypertension induces arterial injury in experimental rat and rabbit models and to determine how the combined effects of hypertension and hypercholesterolemia cause acceleration of atherogenesis. The studies on the effects of hypertension on atherosclerosis will utilize the Watanabe Heritable Hyperlipidemic rabbit (WHHL) and controls made hypertensive by either the Goldblatt one-kidney, one-clip technique or by angiotension II infusion. The effects of hypertension and the interactions with hypercholesterolemia on the nature, extent, and severity of aortic, coronary, and cerebral atherosclerosis will be characterized. Gene expressions of selected growth factors and of connective tissue constituents in aorta will be examined serially and their changes correlated with development of cellular and extracellular matrix abnormalities. In this way, we hope to determine how hypertension and hypercholesterolemia alter growth factor expression in the arterial wall and whether such changes cause autocrine or paracrine effects which contribute to the pathologic changes that ensue. We also will test the hypothesis that increased expression of transforming growth factor beta (TGF-beta) in response to hypertension causes changes in extracellular matrix which lead primarily to SMC hypertrophy and that the relative amounts of TGF-beta and other growth factors such as platelet- derived growth factor (PDGF), will determine whether cellular hypertrophy or hyperplasia occurs. The effect of hypertension and the relationship of TGF-beta to the expression of fibronectin and other connective tissue constituents also will be examined to determine its role in connective tissue regulation. Such studies will be performed initially in the rat and then extended to the rabbit. This project is a key component of the SCOR grant and is closely related to several other sections, including Projects II, V, VII, and VIII, which deal with the relationship of hypertension to functional characteristics of vascular cells or arterial tissue. The studies are of particular interest since they involve investigation in vivo of the molecular and cell biology of the artery in clinically-relevant animal models. The data obtained should expand our knowledge and understanding of how hypertension causes macrovascular disease and could lead to improved therapy for preventing clinical complications of atherosclerosis in the hypertensive patient.